tbuckley/cabot-search huggingface dataset:
NCOG-41. REAL WORLD EXPERIENCE WITH TTFIELDS WITH EMPHASIS ON THERAPY COMPLIANCE
Authors: Claudius Jelgersma, Gülsüm Akkas, Joan Alsolivany, David Wasilewski, Bastian Gastl, Peter Vajkoczy, Martin Misch, David Kaul, Lars Bullinger, Julia Onken
Journal: Neuro-Oncology (2023)

Abstract Tumor Treating Fields (TTF) therapy has emerged as a significant adjunctive component in the treatment of high-grade tumors following its validation in the EF-14 trial in 2017. The incorporation of TTF therapy, alongside cyclic temozolomide (TMZ) therapy, has demonstrated enhanced outcomes in terms of PFS and OS when the useage exceeds 18 hours per day (75% compliance rate). Post-hoc analysis of the EF-14 trial has demonstrated that compliance rates exceeding 90% are associated with an additional benefit. Given the cost-intensive nature and significant constraints associated with the therapy, our objective is to generate real-world data on compliance through a retrospective analysis at a high-throughput academic center. Between June 2015 and February 2022, a total of 115 patients were prescribed TTFields as pa rt of their treatment for high-grade glioma. Mean age was 50y and mean preoperative Karnofsky Index 80-90. The average duration of therapy was 8 months. The majority of patients (74%) initiated therapy concurrently with 1st-line treatment, while only 25% managed to start concomitant to the first cycle of temozolomide. 16.7% started TTFields in the 2nd-line and 9.3% in the 3rd-line setting. Thirteen patients discontinued TTFields treatment within the first 3 months and were consequently excluded from further compliance analysis. Across the study cohort, the median compliance rate was 72% (SD 22%), with an average of 41 days of breaks observed. Compliance was highest during the first 3 cycles, with rates of 79%, 73%, and 72%, respectively. Linear regression analysis did not identify any predictors of compliance, including age at surgery, timing of therapy, duration of therapy, gender, and preoperative Karnofsky Index. These findings highlight the importance of monitoring and promoting adherence to TTFields therapy to maximize its potential benefits in the management of high-grade gliomas. Further strategies are warranted to expedite the start of therapy and improve long-term compliance.
NIMG-09. APPLICATION OF FRACTIONAL TUMOR BURDEN MAPPING TO MONITOR GLIOBLASTOMA PROGRESSION IN THE PHASE 1 TRIAL OF GALLIUM MALTOLATE
Authors: Casey Zoss, Jennifer Connelly, Christopher Chitambar, Kathleen Schmainda
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND To address the need for improved glioblastoma (GBM) therapeutics, a Phase 1 trial of gallium maltolate (GaM) for recurrent GBM is ongoing. GaM targets GBM iron metabolism, representing a novel therapeutic mechanism to treat GBM. Monitoring GBM progression is typically accomplished by standard MRI protocols. However, distinguishing progression from treatment effect is often difficult using standard MRI alone; this is especially true for experimental therapeutics. Fractional tumor burden (FTB) mapping incorporates dynamic susceptibility contrast perfusion MRI to generate spatial and quantifiable tumor likelihood estimates. Here, we present three cases from the Phase I trial of GaM to illustrate application of FTB mapping in the clinical trial setting. METHODS Patients enrolled in the GaM trial receive pre-trial baseline imaging and subsequent imaging at 8-week intervals. For each imaging timepoint, an FTB map was created from tissue-validated thresholds of standardized relative cerebral blood volume (sRCBV) in areas of enhancement as determined by pre/post T1 subtraction. RESULTS Case #1 illustrates low FTB-determined tumor probability in a patient with minimal disease who did not progress while on trial for &amp;gt; 33 weeks. Case #2 shows an increase in tumor probability concurrent with radiographic and pathology-confirmed progression soon after initiating GaM. Case #3 demonstrates an increase in tumor probability soon after GaM initiation which preceded an increase in volume by &amp;gt; 10 weeks; GBM progression was confirmed by pathology. CONCLUSIONS The presented cases illustrate the utility of FTB mapping for monitoring GBM progression in the setting of GaM treatment. FTB maps could predict disease progression before standard MRI in some patients. Our experience implicates FTB mapping as an important imaging tool in future GBM clinical trials. The cases add to previous reports that FTB is useful in distinguishing progression from treatment effect with standard treatment regimens.
EPCO-37. DISSECTING GBM EVOLUTION FOLLOWING STANDARD-OF-CARE BY LARGE-SCALE LONGITUDINAL SINGLE NUCLEUS RNA-SEQUENCING
Authors: Masashi Nomura, Avishay Spitzer, Kevin Johnson, Luciano Garofano, Djamel Nehar-Belaid, Young Taek Oh, Kevin J Anderson, Ryan D Najac, Lillian Bussema, Frederick Varn, Fulvio D’Angelo, Tamrin Chowdhury, Simona Migliozzi, Jong Bae Park, Luca Ermini, Anna Golebiewska, Simone Niclou, Sunit Das, Sun Ha Paek, Hyo-Eun Moon, Bertrand Mathon, Anna-Luisa Di Stefano, Franck Bielle, Alice Laurenge, Marc Sanson, Shota Tanaka, Nobuhito Saito, Steve Keir, David Ashley, Jason Huse, W K Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel Verhaak, Mario Suva, Itay Tirosh
Journal: Neuro-Oncology (2023)

Abstract The heterogeneity within tumors has long been associated with therapy failure and disease progression. Recent advances in single-cell RNA-sequencing technologies have enabled us to dissect the cellular diversity in glioblastoma (GBM). However, how these cellular programs change longitudinally under therapy remains poorly understood. To address this question, we collected and profiled a large-scale longitudinal cohort of 59 matched IDH-wildtype GBM sample pairs provided by 7 centers worldwide by single-nucleus RNA-sequencing (snRNA-seq) and whole-exome/whole-genome sequencing. The majority of patients (51 patients) in this cohort received standard-of-care (temozolomide and radiation) following initial tumor resection. Leveraging this large-scale snRNS-seq dataset of 457,442 cells, we detected novel cellular states and associations between malignant and tumor microenvironment (TME) cells, and then performed longitudinal analyses. The recurrent samples showed significantly lower malignant cell fraction (p=0.002) and reciprocal increase in proportions of glio-neuronal TME cell types (oligodendrocytes, neurons and astrocytes). The TME composition, malignant cell state proportions and baseline expression programs were retained at recurrence more than expected by chance, but overall were not well conserved between primary and recurrent samples. A subset of pairs (12/59 pairs) enriched with glio-neuronal TME at recurrence showed a significant transcriptomic shift and was associated with better clinical course (p=0.02). The tumors that acquired radiation-related small deletion phenotype underwent a transition towards MES/Hypoxia phenotype (0/9 at primary, 6/9 at recurrence, p=0.02). We defined pairs as likely responders or non-responders to treatment based on the MGMT methylation status of the primary tumor sample. This uncovered diverging evolutionary trajectories in cellular programs between the two groups. Strikingly, the changes in malignant state frequency and baseline malignant expression profile were strongly associated with specific changes in the TME composition. Our findings based on high-resolution longitudinal snRNA-seq analyses highlight the diverse evolutionary trajectories in GBM that are shaped by TME changes and treatments.
CTIM-15. T CELL RESPONSE DYNAMICS IN PHASE 3 GLIOBLASTOMA PATIENTS IMMUNIZED WITH AUTOLOGOUS DENDRITIC CELLS PULSED WITH AUTOLOGOUS TUMOR CELL LYSATE
Authors: Marnix Bosch, Linda Liau, Keyoumars Ashkan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND 331 glioblastoma patients were immunized with autologous dendritic cells (DCs) pulsed with autologous tumor cell lysate or placebo in a Phase 3 clinical trial. Immunization with the pulsed DCs was associated with extended overall survival in both newly diagnosed and recurrent disease. Objective: To characterize T cell responses and T cell response dynamics in patients immunized with autologous dendritic cells pulsed with autologous tumor cell lysate. METHODS we performed T cell receptor sequencing on peripheral blood mononuclear cells from both newly diagnosed and recurrent glioblastoma patients that were treated with the pulsed DCs. Timepoints from both before and after immunization were compared to understand T cell response dynamics. RESULTS Expansion of several hundred new T cell clones as well as more than 700 previously detected T cell clones was detected over time in both newly diagnosed and recurrent GBM patients who were treated with the pulsed DCs. Investigation of the dynamics of the response demonstrated that further expansion was triggered by ongoing immunizations. Correlations between T cell response data and clinical outcomes are ongoing. CONCLUSION Immunization with autologous DCs pulsed with autologous tumor cell lysate induces broad spectrum immune responses in patients with glioblastoma.
CNSC-10. GLIOBLASTOMA CELLS IMITATE NEURON’S EXCITABILITY IN ACUTE AND ORGANOTYPIC HUMAN BRAIN SLICES
Authors: Tong Tong, Attila Ozsvar, Wen-Hsien Hou, Anders Korshøj
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly lethal cancer due to its inter- and intra-patient molecular and physiological heterogeneity, and its complex interaction with brain tissue. Recent findings demonstrate that Neuron-to-brain tumor-synaptic-communications (NBTSCs) engage in a vicious cycle of enhanced neuronal activity, driving glioma progression and invasion and tumor-induced epilepsy. However, the physiology of these synaptic interactions in the tumor-infiltrated human neocortex remains largely uncharacterized. To address this gap, our study focused on investigating the intrinsic electrical properties of glioma cells and NBTSCs in the tumor-infiltrated human cortex using a unique experimental workflow involving acute and cultured human tumor-infiltrated brain slices. Via an adeno-associated virus-assisted gene delivery technique, we selectively express fluorescence proteins in a cell-type specific manner. By performing fluorescence-guided whole-cell patch clamp recording, we characterized the electrophysiological properties of glioma cells and neurons under the tumor microenvironment. We observed that glioma cells from tumor-infiltrated human brain samples displayed depolarized resting membrane potential (-32.21 ± 2.1mV) and high input resistance (1.24 ± 0.18 GΩ). Approximately 69.2% of glioma cells exhibited spikelets or distorted-action potentials upon current injection. Consistent with other studies, a subset of glioma cells (11.8%) exhibited spontaneous excitatory postsynaptic currents (sEPSC). In addition, the tumor-infiltrated microenvironment significantly influences the proximal neurons’ physiology and the neuronal microcircuitry, leading to abnormal intrinsic electrical properties, depolarized resting membrane potential (-37.66 ± 4.32 mV), and a significant reduction in spontaneous synaptic input frequency. Collectively, our study consolidates the existence of NBTSCs in human cancer patients and reveals that glioma cells exhibit neuron-like excitability, which is contrary to the common understanding that they are considered as non-excitable. Under the tumor microenvironment, neurons display hyperexcitability. Our newly established organotypic human brain slice culture platform provides potential grounds for exploring further the biological characteristics of gliomas and NBTSCs.
RADT-15. INTRACRANIAL OUTCOMES OF DUAL IMMUNE-CHECKPOINT INHIBITION AND SRS COMBINATION IN PATIENTS WITH MELANOMA AND NSCLC BRAIN METASTASES
Authors: Eugene Vaios, Rachel Shenker, Peter Hendrickson, Zihan Wan, Donna Niedzwiecki, Sebastian F Winter, Jorg Dietrich, April Salama, Jeffrey Clarke, Karen Allen, Trey Mullikin, Scott Floyd, John Kirkpatrick, Zachary Reitman
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION The intracranial benefit of offering dual immune checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to melanoma and non-small cell lung cancer (NSCLC) patients receiving SRS for brain metastases is unknown. We hypothesized that D-ICPI improves local control compared to SRS alone. METHODS Melanoma and NSCLC patients treated with SRS between 2016-2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence (LR), intracranial progression (IP), and overall survival (OS) were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. RESULTS 288 patients (44% melanoma, 56% NSCLC) with 1,704 brain metastases were included. 53% of patients had symptomatic metastases. Median follow up was 58.8 months. Patients were treated with D-ICPI (28%), S-ICPI (45%), or SRS alone (27%). 12-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95%CI:91.11-96.90%), 91.72% (89.29-93.64%), and 88.22% (84.06-91.41%). Only D-ICPI was significantly associated with reduced LR (p = 0.0032). 173 patients (60%) developed IP. The 12-month cumulative incidence of IP was 41.27% (95%CI:30.27-51.92%), 51.86% (42.78-60.19%), and 57.15% (44.98-67.59%) following D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (p = 0.0408). On multivariate Cox regression, D-ICPI (HR:0.595,95%CI:0.373-0.951,p = 0.0300) and presentation with &amp;gt;10 BMs (2.492,1.68-3.725,p &amp;lt; .0001) remained significantly correlated with IP. Median OS following D-ICPI, S-ICPI, and SRS alone was 26.1 (95%CI:15.5-40.7), 21.5 (16.5-29.6) and 17.5 (11.3-23.8) months. Only D-ICPI trended toward improved OS (p = 0.0772). S-ICPI, fractionation, and timing of immunotherapy were not predictive of clinical outcomes. CONCLUSIONS The addition of D-ICPI for melanoma and NSCLC patients undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for symptomatic brain metastasis patients, regardless of fractionation or immunotherapy timing. Toxicity with this combination should be evaluated and balanced against clinical benefits.
CTNI-84. PNOC022: A COMBINATION THERAPY TRIAL USING AN ADAPTIVE PLATFORM DESIGN FOR PATIENTS WITH DIFFUSE MIDLINE GLIOMAS (DMGS) AT INITIAL DIAGNOSIS, POST-RADIATION THERAPY AND AT TIME OF PROGRESSION
Authors: Cassie Kline, Andrea Franson, Anu Banerjee, Alyssa T Reddy, Shannon Raber, Carly Hoffman, Jane Minturn, Jasper van der Lugt, E de Vos-Kerkhof, Dannis van Vuurden, Nicolas Gerber, Ana Guerreiro Stuecklin, Lindsay Kilburn, Jennifer Elster, Nicholas Whipple, Kenneth Cohen, Michal Yalon Oren, Sharon Gardner, Andrew Cluster, Susan Chi, Daniel Landi, Geoffrey McCowage, Adam Resnick, Joanna Phillips, Aashim Bhatia, Arastoo Vossough, Elizabeth George, Ali Nabavizadeh, Steve Braunstein, Nalin Gupta, Michael Prados, Sebastian Waszak, Janel Boyle-Lang, Annette Molinaro, Matthew Dun, Carl Koschmann, Javad Nazarian, Sabine Mueller
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Subjects diagnosed with diffuse midline glioma (DMG) face extremely poor prognoses. PNOC DMG-ACT (DMG-Adaptive Combination Trial, PNOC022) is an open-label, multi-institutional, international trial that aims to investigate combination therapies for patients with DMG. Herein, we report on the combination study arm with ONC201, an orally available DRD2 and ClpP agonist, and paxalisib, a dual PI3K-mTOR inhibitor for patients who completed standard-of-care radiation (Cohort 2). METHODS Children and young adults aged 2-39 years were enrolled 4-14 weeks post-radiation and received maintenance therapy with weekly ONC201 (weight-based adult equivalent of 625 mg) and daily paxalisib (27mg/m2). Plasma and CSF samples for pharmacokinetics (PK) and circulating tumor DNA (ctDNA) were collected at multiple timepoints. RESULTS Sixty-eight patients with biopsy-proven DMG enrolled between November 2021 and June 2023 (median age 9 years [range 3-37], n=41 female [60%]). Site-determined tumor location includes 47 pontine (69%), 16 thalamic (24%), 3 spinal cord (4%) and 2 cerebellar (2%) DMGs. Median overall survival (OS) from time of diagnosis is 16.5 months (lower 95% CI 11.6 months) with a median follow-up time of 9.9 months (95% CI: 8.5, 11.4). The H3K27M mutation was found in 91% (n=50) and 9% were classified as H3K27-altered (n=5). TP53 was mutant in 50% (22/44 available). Most common grade 3 and above treatment-related adverse events were neutrophil count decreased (n=4); mucositis (n=3); and, colitis, DRESS, lymphocyte count decreased, hyperglycemia, hypokalemia (n=2). PK and ctDNA analyses are being finalized. CONCLUSIONS The current median OS is encouraging compared to historical controls. At the meeting, we will present updated molecular characterization and early biological correlates in association with clinical outcomes including toxicity, OS, PK, and central imaging confirmed progression-free survival.
NIMG-11. AUTOPSY-BASED RADIO-PATHOMIC MAPS OF TISSUE COMPOSITION DELINEATE IDH1 STATS IN GLIOMAS
Authors: Samuel Bobholz, Allison Lowman, Savannah Duenweg, Aleksandra Winiarz, Margaret Stebbins, Michael Flatley, Biprojit Nath, Fitzgerald Kyereme, Jennifer Connelly, Dylan Coss, Max Krucoff, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2023)

Abstract Isocitrate dehydrogenase 1 (IDH1) mutation status is used as an important prognostic marker for gliomas, where IDH1-wildtype patients see shorter survival than patients with an IDH1 mutation. This study uses radio-pathomic maps of cell, extracellular fluid (ECF), and cytoplasm (Cyt) density developed using conventional MRI and aligned autopsy samples to test the hypothesis that IDH1-mutant tumors differ in contrast-enhancing and non-enhancing tissue composition from IDH1-wildtype tumors. A total of 426 patients from the UCSF-PDGM data set (380 IDH1-wildtype, 46 IDH1-mutant) were included in this study. T1, T1C, FLAIR and ADC images from each patient’s pre-surgical MRI were used to generate whole brain radio-pathomic maps of cell, ECF, and Cyt density using a previously reported algorithm. This tool was trained using aligned autopsy samples as ground truth and is particularly adept at highlighting areas of tumor beyond traditional imaging signatures. The mean value from each feature map was computed for each patient both within non-necrotic contrast enhancement and non-enhancing FLAIR hyperintensity. Higher ECF density (F=15.45, p&amp;lt; 0.001) and lower Cyt density (F=8.51, p=0.004) was observed within contrast-enhancement for IDH1 mutant patients, with no difference observed for cell density within contrast enhancement between mutation statuses (F=0.03, p=0.86). Higher cell density (F=4.16, p&amp;lt; 0.042), Higher ECF density (F=4.65, p=0.032), lower Cyt density (F=4.48, p=0.035) was also found in patients with IDH1 mutations in the non-enhancing FLAIR hyperintense region. These results suggest that the large-scale tissue composition of IDH1-mutant tumors may differ from IDH1-wildtype tumors, suggesting differences in growth patterns and pathological composition between tumor types. Future studies examining how tissue composition post-treatment over time may elucidate how pathological characteristics evolve for each tumor type.
BIOM-04. IMPROVEMENT OF LEPTOMENINGEAL DISEASE (LMD) WITH MEK AND BRAF INHIBITORS, CRANIOSPINAL IRRADIATION (CSI), AND INTRATHECAL (IT) CHEMOTHERAPY IN ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA (PXA)
Authors: Joshua Nahm, Mia Vu, Eva Highberg Schumann, Meenakshi Bhattacharjee, Angel Blanco, Nitin Tandon, Jay-Jiguang Zhu
Journal: Neuro-Oncology (2023)

Abstract Anaplastic pleomorphic xanthoastrocytomas (aPXA) are rare gliomas with a five-year survival of 57%. Standard treatment involves maximal safe resection followed by radiotherapy. BRAF mutation is frequently seen in these patients and is a promising target with concurrent BRAF and MEK inhibitors. However, there is no standard treatment for patients with aPXA and leptomeningeal disease (LMD). Literature review identified four cases with overall survivals (OS) of 3, 4, 18, and 66 months, respectively. We report a 23-year-old female who presented with headache, nausea, vomiting, and aphasia with MRI evidence of a left temporal lobe enhancing mass. Her tumor was initially diagnosed as epithelioid glioblastoma, WHO grade IV after craniotomy. She received concurrent radiation and temozolomide with subsequent 12 cycles of TMZ. After identification of BRAF V600E mutation by next generation sequencing, we revisited her diagnosis, and it was changed to aPXA. Three years later, she presented to the ER with aphasia, headache, weakness, nausea, and vomiting with MRI evidence of hydrocephalus and LMD by brain and spine MRI as well as cerebrospinal fluid analysis. Her treatment regimen consisted of the MEK inhibitor cobimetinib, the BRAF inhibitor vemurafenib, partial craniospinal irradiation (CSI), and intrathecal (IT) chemotherapy with methotrexate, topotecan, cytarabine, and thiotepa sequentially. She is currently doing well with mild bilateral leg weakness. She continues on therapy with BRAF and MEK inhibitors. Her OS is 56 months. Adverse events (AE) were tabulated according to the Common Terminology Criteria for Adverse Events Version 5.0 and included grade IV neutropenia, grade III anemia, grade II rash acneiform, and grade II nausea/vomiting. All AEs were manageable and reversible. Despite the limitations of a case report and retrospective review, our findings suggest that MEK and BRAF inhibitors, CSI, and IT chemotherapy may be effective treatment options for patients with aPXA and LMD.
STEM-04. FATE-BASED CONVERSION FOR IN SITU VACCINATION IN GLIOBLASTOMA
Authors: David Tran, Tianyi Liu, Dan Jin, Son Le, Dongjiang Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Although immune checkpoint inhibitors have shown high benefit for other solid tumors, their efficacy is limited in GBM due in large part to the “cold” tumor microenvironment (TME) of the GBM tumor. New approaches are necessary to overcome these challenges. We propose a shift in the scientific and treatment paradigm of cancer immunotherapy, calling for tumor cells to take on a central, active role in initiating their own immunity right in the TME. METHODS Using AI, we identified cell fate determinants (CFDs) to convert GBM cells directly into induced dendritic cells (iDC) inside the TME. CFDs were delivered using a viral vector and conversion assessed by immunophenotyping, scRNA-seq, and functional assays for classical DC properties. RESULTS A four-CFD subnetwork anchored by PU.1 was sufficient to convert mouse GBM cells to iDCs (CD45+MHCII+CD80/86+MHCI+). iDCs are growth arrested, exhibit 3-fold higher phagocytic activity and upregulate the canonical antigen processing and presenting machineries by 10-40-fold, resulting in 100-fold greater efficiency at processing ovalbumin and cross-presenting SIINFEKL to naive OTI-CD8+ cytotoxic T lymphocytes (CTL). In addition, iDCs efficiently cross-present exogenous antigens to naïve CD8+ CTLs and elicit &amp;gt;30-fold higher activation and cytotoxicity in tumor-specific T cells compared to native GBM cells, confirming their DC-like properties. Lastly, intratumoral GBM-DC conversion in a syngeneic orthotopic GBM model resulted in significant reduction in tumor burden and increase in survival compared to controls (Log-rank, p = 0.01) with synergistic efficacy with ICIs and classical DC-based tumor vaccination. We have also successfully converted human GBM cells to iDCs with similar properties using a 2-CFD combination also anchored by PU.1. CONCLUSIONS GBM-derived iDCs acquired DC-like functions and were capable of eliciting robust intratumor immune activation, thereby overcoming many current limitations of immunotherapy in GBM. Our goal is to develop a low cost, off-the-shelf gene therapy-based fate conversion tumor immunotherapy.